Assessment of affinities of beta-CIT, beta-CIT-FE, and beta-CIT-FP for monoamine transporters permanently expressed in cell lines.
We investigated the effects of three cocaine analogs, beta-CIT (2-beta-carbomethoxy-3-beta-(4-iodophenyl)-tropane), beta-CIT-FE (2-beta-carbomethoxy-3-beta-(4-iodophenyl)-N-(2.fluoroethyl)-nortropa  ne), and beta-CIT-FP (2-beta-carbomethoxy-3-beta-(4-iodophenyl)-N-(3-fluoropropyl)-n ortropane), on the uptake of [3H]dopamine(DA), serotonin(5-HT), and 1-norepinephrine (NE) using cell lines permanently expressing DA, 5-HT, and NE transporters, respectively, to determine their affinities for these three transporters. We generated cell lines stably expressing DA, 5-HT, and NE transporters, respectively, by the Chen-Okayama method, and then tested the abilities of (-)cocaine, beta-CIT, beta-CIT-FE, beta-CIT-FP, and clomipramine to inhibit the uptake of [3H]DA, 5-HT, and 2-NE. Ki values of beta-CIT, beta-CIT-FE, and beta-CIT-FP for [3H]DA, 5-HT, 1-NE uptake were 6, 29, and 33 nM, 91, 133, and 130 nM, and 28, 113 and 70 nM, respectively, whereas those of cocaine and clomipramine were 316, 581, and 176 nM and > 10,000, 437, and 851 nM, respectively. Beta-CIT, beta-CIT-FE, and beta-CIT-FP were shown to be potent DA, 5-HT, and NE uptake inhibitors. Beta-CIT and beta-CIT-FP were highly potent and selective dopamine uptake inhibitors, and therefore might be useful for imaging of DA transporter with single photon emission computed tomography (SPECT) or positron emission tomography (PET).
Okada
T
T
Division of Tracer Kinetics, Biomedical Research Center, Osaka University Medical School, Japan.
Fujita
M
M
Shimada
S
S
Sato
K
K
Schloss
P
P
Watanabe
Y
Y
Itoh
Y
Y
Tohyama
M
M
Nishimura
T
T
D000818:Animals; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D003042:Cocaine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism / Q000493:pharmacokinetics; D050483:Dopamine Plasma Membrane Transport Proteins; D006801:Humans; D007457:Iodine Radioisotopes; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009638:Norepinephrine / Q000378:metabolism / Q000493:pharmacokinetics; D050484:Norepinephrine Plasma Membrane Transport Proteins; D009662:Nortropanes / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000378:metabolism / Q000493:pharmacokinetics; D050486:Serotonin Plasma Membrane Transport Proteins; D027981:Symporters; D014162:Transfection; D014316:Tritium; D014326:Tropanes / Q000378:metabolism* / Q000494:pharmacology
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C097058:N-(2-fluoroethyl)-2-carbomethoxy-3-(4-iodophenyl)nortropane; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D009662:Nortropanes; C493227:SLC6A2 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C493226:Slc6a2 protein, rat; C493232:Slc6a4 protein, rat; D027981:Symporters; D014326:Tropanes; D014316:Tritium; C087552:2-carbomethoxy-8-(3-fluoropropyl)-3-(4-iodophenyl)tropane; D012701:Serotonin; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; D003042:Cocaine; D004298:Dopamine; D009638:Norepinephrine